Identification of Tecovirimat Resistance-Associated Mutations in Human Monkeypox Virus - Los Angeles County

Garrigues, Jacob M.; Hemarajata, Peera; Karan, Abraar; Shah, Naman K.; Alarcón, Jemma; Marutani, Amy N.; Finn, Lauren E.; Smith, T.; Gigante, Crystal M.; Davidson, Whitni; Wynn, Nhien T.; Hutson, Christina L.; Kim, Moon J.; Terashita, Dawn; Balter, Sharon; Green, Nicole M.

doi:10.1128/aac.00568-23

Cited by 20 publications

(21 citation statements)

References 9 publications

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“…Consequently, treatment strategies that consider these factors such as multi‐course antiviral therapy should be developed 16 . Our study confirmed the presence of tecovirimat‐resistant mutations initially identified in B.1 clade 13 . This resistance was also apparent in clade C.1, which was predominant in Korea following the cessation of PHEIC.…”

Section: Discussionsupporting

confidence: 85%

Prolonged viral shedding in an immunocompromised Korean patient infected with hMPXV, sub‐lineage B.1.3, with acquired drug resistant mutations during tecovirimat treatment

Lee,

Choi,

Kim

et al. 2024

Journal of Medical Virology

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Following the worldwide surge in mpox (monkeypox) in 2022, cases have persisted in Asia, including South Korea, and sexual contact is presumed as the predominant mode of transmission, with a discernible surge in prevalence among immunocompromised patients. Drugs such as tecovirimat can result in drug‐resistant mutations, presenting obstacles to treatment. This study aimed to ascertain the presence of tecovirimat‐related resistant mutations through genomic analysis of the monkeypox virus isolated from a reported case involving prolonged viral shedding in South Korea. Here, tecovirimat‐resistant mutations, previously identified in the B.1 clade, were observed in the B.1.3 clade, predominant in South Korea. These mutations exhibited diverse patterns across different samples from the same patient and reflected the varied distribution of viral subpopulations in different anatomical regions. The A290V and A288P mutant strains we isolated hold promise for elucidating these mechanisms, enabling a comprehensive analysis of viral pathogenesis, replication strategies, and host interactions. Our findings imply that acquired drug‐resistant mutations, may present a challenge to individual patient treatment. Moreover, they have the potential to give rise to transmitted drug‐resistant mutations, thereby imposing a burden on the public health system. Consequently, the meticulous genomic surveillance among immunocompromised patients, conducted in this research, assumes paramount importance.

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Section: Discussionsupporting

confidence: 85%

Prolonged viral shedding in an immunocompromised Korean patient infected with hMPXV, sub‐lineage B.1.3, with acquired drug resistant mutations during tecovirimat treatment

Lee,

Choi,

Kim

et al. 2024

Journal of Medical Virology

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“…20 In the context of mpox therapy, mounting evidence shows emergence of tecovirimat-resistant mpox strains accompanied by therapy failure in patients. 15 Here we show that TFT remains highly effective against a tecovirimat-resistant mpox strain.…”

Section: Discussionmentioning

confidence: 65%

“…Although drug antagonism is not desirable, the drug combinations might remain beneficial in preventing the selection of drug resistant mutations 20 . In the context of mpox therapy, mounting evidence shows emergence of tecovirimat‐resistant mpox strains accompanied by therapy failure in patients 15 . Here we show that TFT remains highly effective against a tecovirimat‐resistant mpox strain.…”

Section: Discussionmentioning

confidence: 65%

“…We have recently selected a tecovirimat‐resistant mpox strain, MPXV1 R Teco, by one‐round selection in cell culture in the presence of 4 µM of tecovirimat 8 . Importantly, the two mutations N267D and I372N detected in MPXV1 R Teco were also present in patients from the 2022 outbreak that received tecovirimat treatment and had shown phenotypically confirmed resistance 15 (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…1 Worryingly, an increasing number of studies have reported on the development of tecovirimat resistance in mpox-infected patients during the recent outbreak. 14,15 In addition, TFT eye drops have been applied in a clinical setting for therapy of ophthalmic mpox infection. 4 TFT is a nucleoside analog, which has been approved for other ophthalmic conditions like herpes simplex keratitis.…”

Section: Discussionmentioning

confidence: 99%

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Trifluridine for treatment of mpox infection in drug combinations in ophthalmic cell models

Cinatl,

Bechtel,

Reus

et al. 2024

Journal of Medical Virology

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The Mpox virus can cause severe disease in the susceptible population with dermatologic and systemic manifestations. Furthermore, ophthalmic manifestations of mpox infection are well documented. Topical trifluridine (TFT) eye drops have been used for therapy of ophthalmic mpox infection in patients, however, its efficacy against mpox virus infection in this scenario has not been previously shown. In the present study, we have established ophthalmic cell models suitable for the infection with mpox virus. We show, that TFT is effective against a broad range of mpox isolates in conjunctival epithelial cells and keratocytes. Further, TFT remained effective against a tecovirimat‐resistant virus strain. In the context of drug combinations, a nearly additive effect was observed for TFT combinations with brincidofovir and tecovirimat in conjunctival epithelial cells, while a slight antagonism was observed for both combinations in keratocytes. Altogether, our findings demonstrate TFT as a promising drug for treatment of ophthalmic mpox infection able to overcome tecovirimat resistance. However, conflicting results regarding the effect of drug combinations with approved compounds warrant close monitoring of such use in patients.

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Clinical considerations on monkeypox antiviral medications: An overview

Pourkarim,

Entezari‐Maleki

2023

Pharmacology Res & Perspec

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Monkeypox (mpox), a virus belonging to the orthopoxvirus family, can cause a zoonotic infectious disease with morbidity and cosmetic complications. Therefore, effective antiviral drugs with appropriate safety profiles are important for the treatment of patients with mpox. To date, there is no FDA‐approved drug for the treatment of mpox. However, tecovirimat, brincidofovir, and cidofovir are the candidate therapies for the management of mpox. Given the safety concerns following the use of these medications, we aimed to review evidence on the clinical considerations of mpox antiviral medications that will be useful to guide clinicians in the treatment approach. Based on the current evidence, tecovirimat has favorable clinical efficacy, safety, and side effect profile and it can be considered as first‐line treatment for mpox.

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Identification of Tecovirimat Resistance-Associated Mutations in Human Monkeypox Virus - Los Angeles County

Cited by 20 publications

References 9 publications

Prolonged viral shedding in an immunocompromised Korean patient infected with hMPXV, sub‐lineage B.1.3, with acquired drug resistant mutations during tecovirimat treatment

Prolonged viral shedding in an immunocompromised Korean patient infected with hMPXV, sub‐lineage B.1.3, with acquired drug resistant mutations during tecovirimat treatment

Trifluridine for treatment of mpox infection in drug combinations in ophthalmic cell models

Clinical considerations on monkeypox antiviral medications: An overview

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