{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T09:52:36Z","timestamp":1787997156372,"version":"build-2784847793"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Fund of Seoul St. Mary\u2019s Hospital, The Catholic University of Korea","award":["ZC22SISI0441"],"award-info":[{"award-number":["ZC22SISI0441"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.<\/jats:p>","DOI":"10.3390\/v15061286","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T02:01:15Z","timestamp":1685498475000},"page":"1286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4406-2521","authenticated-orcid":false,"given":"Seungwan","family":"Chae","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Genetic Laboratory Center, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-8177","authenticated-orcid":false,"given":"Hoon Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Genetic Laboratory Center, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Yeon","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Hematology Hospital, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2800-636X","authenticated-orcid":false,"given":"Dukhee","family":"Nho","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Hematology Hospital, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1168-3666","authenticated-orcid":false,"given":"Raeseok","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Hematology Hospital, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-0641","authenticated-orcid":false,"given":"Dong-Gun","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Hematology Hospital, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8632-0168","authenticated-orcid":false,"given":"Myungshin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Genetic Laboratory Center, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Catholic Genetic Laboratory Center, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e00027-20","DOI":"10.1128\/CMR.00027-20","article-title":"Beyond Cytomegalovirus and Epstein-Barr Virus: A Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients","volume":"33","author":"Zanella","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.jmii.2019.07.001","article-title":"Clinical significance of post-treatment viral load of cytomegalovirus in patients with hematologic malignancies","volume":"54","author":"Lu","year":"2021","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jcv.2018.09.019","article-title":"Biological relevance of Cytomegalovirus genetic variability in congenitally and postnatally infected children","volume":"108","author":"Galitska","year":"2018","journal-title":"J. Clin. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s12250-017-4055-y","article-title":"Detection of congenital cytomegalovirus in newborns using nucleic acid amplification techniques and its public health implications","volume":"32","author":"Liu","year":"2017","journal-title":"Virol. Sin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.idc.2019.02.008","article-title":"Cytomegalovirus Infections of the Stem Cell Transplant Recipient and Hematologic Malignancy Patient","volume":"33","author":"Pande","year":"2019","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.jiac.2022.05.020","article-title":"Intra-host diversity of drug-resistant cytomegalovirus: A case report of cytomegalovirus infection after allogeneic hematopoietic cell transplantation","volume":"28","author":"Jung","year":"2022","journal-title":"J. Infect. Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e13089","DOI":"10.1111\/tid.13089","article-title":"Cytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation","volume":"21","author":"Kolve","year":"2019","journal-title":"Transpl. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1182\/blood.V75.9.1888.1888","article-title":"Cytomegalovirus infection after autologous bone marrow transplantation: Occurrence of cytomegalovirus disease and effect on engraftment","volume":"75","author":"Reusser","year":"1990","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.bbmt.2010.03.020","article-title":"Evidence for a Bidirectional Relationship between Cytomegalovirus Replication and acute Graft-versus-Host Disease","volume":"16","author":"Cantoni","year":"2010","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1111\/ajt.15515","article-title":"Cytomegalovirus (CMV) infection and risk of mortality in allogeneic hematopoietic stem cell transplantation (Allo-HSCT): A systematic review, meta-analysis, and meta-regression analysis","volume":"19","author":"Torres","year":"2019","journal-title":"Am. J. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1016\/S2352-3026(15)00289-6","article-title":"Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: A retrospective cohort study","volume":"3","author":"Green","year":"2016","journal-title":"Lancet Haematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1016\/S1473-3099(19)30107-0","article-title":"Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)","volume":"19","author":"Ljungman","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1056\/NEJMoa1706640","article-title":"Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation","volume":"377","author":"Marty","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1128\/CMR.12.2.286","article-title":"Resistance of human cytomegalovirus to antiviral drugs","volume":"12","author":"Erice","year":"1999","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/jac\/dkq368","article-title":"Drug-resistant cytomegalovirus in transplant recipients: A French cohort study","volume":"65","author":"Hantz","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.antiviral.2016.04.002","article-title":"Identification of resistance-associated HCMV UL97- and UL54-mutations and a UL97-polymporphism with impact on phenotypic drug-resistance","volume":"131","author":"Fischer","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/rmv.1873","article-title":"Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: Current state of the art","volume":"26","author":"Campos","year":"2016","journal-title":"Rev. Med. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1128\/AAC.00511-13","article-title":"Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance","volume":"57","author":"Chou","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1128\/JCM.02205-14","article-title":"Characterization of multiple cytomegalovirus drug resistance mutations detected in a hematopoietic stem cell transplant recipient by recombinant phenotyping","volume":"52","author":"Drouot","year":"2014","journal-title":"J. Clin. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S72","DOI":"10.1093\/jpids\/piy104","article-title":"Cytomegalovirus in Pediatric Hematopoietic Stem Cell Transplantation: A Case-Based Panel Discussion of Current Challenges","volume":"7","author":"Englund","year":"2018","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1182\/blood.2019000956","article-title":"How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation","volume":"135","author":"Einsele","year":"2020","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1182\/blood-2016-06-688432","article-title":"How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients","volume":"128","author":"Shah","year":"2016","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1093\/cid\/ciy696","article-title":"Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials","volume":"68","author":"Chemaly","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1086\/338362","article-title":"Cytomegalovirus UL97 Phosphotransferase Mutations That Affect Susceptibility to Ganciclovir","volume":"185","author":"Chou","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1007\/s40121-021-00452-4","article-title":"Cytomegalovirus Infection and the Implications of Drug-Resistant Mutations in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Retrospective Study from a Tertiary Hospital in China","volume":"10","author":"Yu","year":"2021","journal-title":"Infect. Dis. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1093\/infdis\/jit475","article-title":"High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation","volume":"209","author":"Shmueli","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/s41409-018-0257-7","article-title":"Clinical and genotypic CMV drug resistance in HSCT recipients: A single center epidemiological and clinical data","volume":"54","author":"Vejrazkova","year":"2019","journal-title":"Bone Marrow Transplant."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41409-018-0191-8","article-title":"Refractory cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation: When should genotypic drug resistance testing be requested?","volume":"53","author":"Solano","year":"2018","journal-title":"Bone Marrow Transplant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1086\/342844","article-title":"Analysis and Characterization of Antiviral Drug\u2013Resistant Cytomegalovirus Isolates from Solid Organ Transplant Recipients","volume":"186","author":"Lurain","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.humimm.2004.02.007","article-title":"Clinical and biologic aspects of human cytomegalovirus resistance to antiviral drugs","volume":"65","author":"Baldanti","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.antiviral.2016.10.016","article-title":"Genotypic resistance of cytomegalovirus to antivirals in hematopoietic stem cell transplant recipients from Portugal: A retrospective study","volume":"138","author":"Campos","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104711","DOI":"10.1016\/j.antiviral.2020.104711","article-title":"Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance","volume":"176","author":"Chou","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E4120","DOI":"10.1073\/pnas.1501880112","article-title":"Limits and patterns of cytomegalovirus genomic diversity in humans","volume":"112","author":"Renzette","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.jmii.2021.01.007","article-title":"Molecular Epidemiology of Cytomegalovirus UL97 and UL54 variants in Taiwan","volume":"54","author":"Yang","year":"2021","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/CMR.00009-10","article-title":"Antiviral Drug Resistance of Human Cytomegalovirus","volume":"23","author":"Lurain","year":"2010","journal-title":"Clin. Microbiol. Rev."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/6\/1286\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:45:34Z","timestamp":1760125534000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/6\/1286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["v15061286"],"URL":"https:\/\/doi.org\/10.3390\/v15061286","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]}}}