Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Kovar L[original query] |
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Tecovirimat resistance in Mpox patients, United States, 2022-2023
Smith TG , Gigante CM , Wynn NT , Matheny A , Davidson W , Yang Y , Condori RE , O'Connell K , Kovar L , Williams TL , Yu YC , Petersen BW , Baird N , Lowe D , Li Y , Satheshkumar PS , Hutson CL . Emerg Infect Dis 2023 29 (12) 2426-2432 During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.com) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat. |
Resistance to anti-orthopoxviral drug tecovirimat (TPOXX) during the 2022 mpox outbreak in the US (preprint)
Smith TG , Gigante CM , Wynn NT , Matheny A , Davidson W , Yang Y , Condori RE , O'Connell K , Kovar L , Williams TL , Yu YC , Petersen BW , Baird N , Lowe D , Li Y , Satheshkumar PS , Hutson CL . medRxiv 2023 18 Background: During the 2022 multinational outbreak of monkeypox virus (MPXV) clade IIb, the antiviral drug tecovirimat (TPOXX) was deployed in the US on a large scale for the first time ever. The MPXV F13L gene homolog encodes the target of tecovirimat, and single amino acid changes in the F13 protein are known to cause resistance to tecovirimat in orthopoxviruses (OPXV). Method(s): Whole genome metagenomic sequencing and amplicon-based sequencing targeting the F13L gene was used to identify nine mutations previously reported to cause resistance in other OPXV along with ten novel mutations that have been identified from the 2022 mpox outbreak. A cytopathic effect assay, previously established at CDC as part of WHO smallpox research, was adapted to MPXV for tecovirimat phenotype testing of virus isolated from mpox patients. Result(s): As of March 2023, in total, 70 isolates from 40 patients were tested, and 50 of these isolates from 26 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of TPOXX treatment; while isolates with F13 mutations identified by routine surveillance of patients not treated with TPOXX have remained sensitive. Conclusion(s): These data indicate that tecovirimat resistance is developing in immunocompromised patients treated with TPOXX and that for isolates that we have analyzed, the frequency of resistant viruses remain relatively low (< 1%) compared to the total number of patients treated with TPOXX. These findings inform our understanding of when tecovirimat resistance is likely to occur and highlight the need for additional OPXV therapeutics. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Genomic deletions and rearrangements in monkeypox virus from the 2022 outbreak, USA (preprint)
Gigante CM , Plumb M , Ruprecht A , Zhao H , Wicker V , Wilkins K , Matheny A , Khan T , Davidson W , Sheth M , Burgin A , Burroughs M , Padilla J , Lee JS , Batra D , Hetrick EE , Howard DT , Garfin J , Tate L , Hubsmith SJ , Mendoza RM , Stanek D , Gillani S , Lee M , Mangla A , Blythe D , SierraPatev S , Carpenter-Azevedo K , Huard RC , Gallagher G , Hall J , Ash S , Kovar L , Seabolt MH , Weigand MR , Damon I , Satheshkumar PS , McCollum AM , Hutson CL , Wang X , Li Y . bioRxiv 2022 17 Genomic surveillance of monkeypox virus (MPXV) during the 2022 outbreak has been mainly focused on single nucleotide polymorphism (SNP) changes. DNA viruses, including MPXV, have a lower SNP mutation rate than RNA viruses due to higher fidelity replication machinery. We identified a large genomic rearrangement in a MPXV sequence from a 2022 case in the state of Minnesota (MN), USA, from an abnormal, uneven MPXV read mapping coverage profile in whole-genome sequencing (WGS) data. We further screened WGS data of 206 U.S. MPXV samples and found seven (3.4 percent) sequenced genomes contained similar abnormal read coverage profiles that suggested putative large deletions or genomic rearrangements. Here, we present three MPXV genomes containing deletions ranging from 2.3 to 15 kb and four genomes containing more complex rearrangements. Five genomic changes were each only seen in one sample, but two sequences from linked cases shared an identical 2.3 kb deletion in the 3' terminal region. All samples were positive using VAC1 and Clade II (formerly West African)-specific MPXV diagnostic tests; however, large deletions and genomic rearrangements like the ones reported here have the potential to result in viruses in which the target of a PCR diagnostic test is deleted. The emergence of genomic rearrangements during the outbreak may have public health implications and highlight the importance of continued genomic surveillance. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Use of whole genome sequencing to complement characterisation of a typhoid fever outbreak among a Marshallese community: Oklahoma, 2015.
Burnsed LJ , Kovar LD , Angelo KM , Trees EK , Concepcion-Acevedo J , McDermott MD , Wagner D , Bradley KK . Epidemiol Infect 2018 147 1-7 Typhoid fever is an illness caused by Salmonella enterica serotype Typhi. In developing regions, it affects an estimated 20 million people annually, causing 200 000 deaths. Although uncommon, cases occur in the USA each year, predominantly due to international travel. During February 2015, the Oklahoma State Department of Health (OSDH) detected an outbreak of typhoid fever among residents of northwestern Oklahoma. OSDH conducted case-patient interviews to identify the source and symptomatic contacts. Whole genome sequencing (WGS) was performed to characterise the genetic relatedness of isolates among the four outbreak-associated pulsed-field gel electrophoresis (PFGE) patterns. We identified 38 cases, 25 confirmed and 13 probable, in two states. WGS revealed a 0-10 single-nucleotide polymorphism variation between isolates. Although we were unable to determine the source, almost all case-patients were members of the Marshallese community that attended a common event in Oklahoma, or were contacts to a confirmed case. This is the largest outbreak of typhoid fever in the USA since 1989, and first to apply WGS to complement interpretation of PFGE results during a typhoid fever outbreak investigation. This investigation illustrates the potential risk of outbreaks among communities comprised of international populations from regions where typhoid fever remains endemic. |
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