Dual Resistance to Maribavir and Ganciclovir in Transplant Recipients
Abstract
:1. Introduction
2. Methods
2.1. Samples
2.2. Sequencing and Analysis
3. Results
3.1. Frequency of Resistance Mutations by Viral Gene and Anti-Viral Drug
3.2. Frequency of Single and Dual Resistance by Patient Sample
4. Discussion
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
- Chou, S. Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance. Antiviral. Res. 2020, 176, 104711. [Google Scholar] [CrossRef] [PubMed]
- Kotton, C.N.; Kumar, D.; Caliendo, A.M.; Huprikar, S.; Chou, S.; Danziger-Isakov, L.; Humar, A.; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2018, 102, 900–931. [Google Scholar] [CrossRef]
- Razonable, R.R.; Humar, A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transplant. 2019, 33, e13512. [Google Scholar] [CrossRef] [PubMed]
- Yong, M.K.; Shigle, T.L.; Kim, Y.J.; Carpenter, P.A.; Chemaly, R.F.; Papanicolaou, G.A. American Society for Transplantation and Cellular Therapy Series: #4-Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation. Transplant. Cell Ther. 2021, 27, 957–967. [Google Scholar]
- Ljungman, P.; Chemaly, R.F.; Khawaya, F.; Alain, S.; Avery, R.; Badshah, C.; Boeckh, M.; Fournier, M.; Hodowanec, A.; Komatsu, T.; et al. Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum. Clin. Infect. Dis. 2024, 79, 787–794. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Hiskey, L.; Madigan, T.; Ristagno, E.H.; Razonable, R.R.; Ferdjallah, A. Prevention and management of human cytomegalovirus in pediatric HSCT recipients: A review. Front. Pediatr. 2022, 10, 1039938. [Google Scholar] [CrossRef] [PubMed]
- Chou, S.W. Cytomegalovirus drug resistance and clinical implications. Transpl. Infect. Dis 2001, 3 (Suppl. 2), 20–24. [Google Scholar] [CrossRef]
- Lurain, N.S.; Chou, S. Antiviral drug resistance of human cytomegalovirus. Clin. Microbiol. Rev. 2010, 23, 689–712. [Google Scholar] [CrossRef]
- Fisher, C.E.; Knudsen, J.L.; Lease, E.D.; Jerome, K.R.; Rakita, R.M.; Boeckh, M.; Limaye, A.P. Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients. Clin. Infect. Dis. 2017, 65, 57–63. [Google Scholar] [CrossRef]
- Kotton, C.N.; Kamar, N. New Insights on CMV Management in Solid Organ Transplant Patients: Prevention, Treatment, and Management of Resistant/Refractory Disease. Infect. Dis. Ther. 2023, 12, 333–342. [Google Scholar] [CrossRef]
- Kleiboeker, S.B. Prevalence of cytomegalovirus antiviral drug resistance in transplant recipients. Antiviral. Res. 2023, 215, 105623. [Google Scholar] [CrossRef] [PubMed]
- Kleiboeker, S.; Nutt, J.; Schindel, B.; Dannehl, J.; Hester, J. Cytomegalovirus antiviral resistance: Characterization of results from clinical specimens. Transpl. Infect. Dis. 2014, 16, 561–567. [Google Scholar] [CrossRef]
- Chou, S.; Watters, M.; Sinha, R.; Kleiboeker, S. Ganciclovir and maribavir susceptibility phenotypes of cytomegalovirus UL97 ATP binding region mutations detected by expanded genotypic testing. Antiviral. Res. 2021, 14, 105139. [Google Scholar] [CrossRef] [PubMed]
- Boivin, G.; Goyette, N.; Farhan, M.; Ives, J.; Elston, R. Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis. J. Clin. Virol. 2012, 53, 208–213. [Google Scholar] [CrossRef] [PubMed]
- Boivin, G.; Goyette, N.; Rollag, H.; Jardine, A.G.; Pescovitz, M.D.; Asberg, A.; Ives, J.; Hartmann, A.; Humar, A. Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antiviral. Ther. 2009, 14, 697–704. [Google Scholar] [CrossRef]
- Hantz, S.; Garnier-Geoffroy, F.; Mazeron, M.C.; Garrigue, I.; Merville, P.; Mengelle, C.; Rostaing, L.; Saint Marcoux, F.; Essig, M.; Rerolle, J.P.; et al. Drug-resistant cytomegalovirus in transplant recipients: A French cohort study. J. Antimicrob. Chemother. 2010, 65, 2628–2640. [Google Scholar] [CrossRef]
- Myhre, H.A.; Haug Dorenberg, D.; Kristiansen, K.I.; Rollag, H.; Leivestad, T.; Asberg, A.; Hartmann, A. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation 2011, 92, 217–223. [Google Scholar] [CrossRef]
- Young, P.G.; Rubin, J.; Angarone, M.; Flaherty, J.; Penugonda, S.; Stosor, V.; Ison, M.G. Ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients: A single-center retrospective cohort study. Transpl. Infect. Dis. 2016, 18, 390–395. [Google Scholar] [CrossRef]
- Lurain, N.S.; Bhorade, S.M.; Pursell, K.J.; Avery, R.K.; Yeldandi, V.V.; Isada, C.M.; Robert, E.S.; Kohn, D.J.; Arens, M.Q.; Garrity, E.R.; et al. Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients. J. Infect. Dis. 2002, 186, 760–768. [Google Scholar] [CrossRef]
- Timpone, J.G.; Yimen, M.; Cox, S.; Teran, R.; Ajluni, S.; Goldstein, D.; Fishbein, T.; Kumar, P.N.; Matsumoto, C. Resistant cytomegalovirus in intestinal and multivisceral transplant recipients. Transpl. Infect. Dis. 2016, 18, 202–209. [Google Scholar] [CrossRef]
- Shmueli, E.; Or, R.; Shapira, M.Y.; Resnick, I.B.; Caplan, O.; Bdolah-Abram, T.; Wolf, D.G. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J. Infect. Dis. 2014, 209, 557–561. [Google Scholar] [CrossRef] [PubMed]
- Allice, T.; Busca, A.; Locatelli, F.; Falda, M.; Pittaluga, F.; Ghisetti, V. Valganciclovir as pre-emptive therapy for cytomegalovirus infection post-allogenic stem cell transplantation: Implications for the emergence of drug-resistant cytomegalovirus. J. Antimicrob. Chemother. 2009, 63, 600–608. [Google Scholar] [CrossRef]
- Boeckh, M.; Ljungman, P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood 2009, 113, 5711–5719. [Google Scholar] [CrossRef] [PubMed]
- Avery, R.K.; Alain, S.; Alexander, B.D.; Blumberg, E.A.; Chemaly, R.F.; Cordonnier, C.; Duarte, R.F.; Florescu, D.F.; Kamar, N.; Kumar, D.; et al. Maribavir for Refractory Cytomegalovirus Infections with or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin. Infect. Dis. 2022, 75, 690–701, Erratum in: Clin. Infect. Dis. 2023, 76, 560. [Google Scholar] [CrossRef] [PubMed]
- Chou, S.; Song, K.; Wu, J.; Bo, T.; Crumpacker, C. Drug resistance mutations and associated phenotypes detected in clinical trials of maribavir for treatment of cytomegalovirus infection. J. Infect. Dis. 2022, 226, 576–584. [Google Scholar] [CrossRef]
- Chou, S.; Wu, J.; Song, K.; Bo, T. Novel UL97 drug resistance mutations identified at baseline in a clinical trial of maribavir for resistant or refractory cytomegalovirus infection. Antiviral. Res 2019, 172, 104616. [Google Scholar] [CrossRef]
- Chou, S.; Alain, S.; Cervera, C.; Chemaly, R.F.; Kotton, C.N.; Lundgren, J.; Papanicolaou, G.A.; Pereira, M.R.; Wu, J.J.; Murray, R.A.; et al. Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients. J. Infect. Dis. 2024, 229, 413–421. [Google Scholar] [CrossRef]
- Fung, M.; DeVoe, C.; Spottiswoode, N.; Doernberg, S.B. Maribavir for cytomegalovirus treatment in the real world-not a silver bullet. Open Forum Infect. Dis. 2022, 10, ofac686. [Google Scholar] [CrossRef]
- Kleiboeker, H.L.; Prom, A.; Paplaczyk, K. Development of cytomegalovirus resistant to maribavir: Real world, real problem? Transpl. Infect. Dis. 2024, 26, e14259. [Google Scholar] [CrossRef]
UL54 | UL97 | |||||||
---|---|---|---|---|---|---|---|---|
Ganciclovir | Ganciclovir | Maribavir | ||||||
Mutation(s) | No. | % | Mutation(s) | No. | % | Mutation(s) | No. | % |
None detected | 1397 | 95.75% | None detected | 1106 | 75.81% | None detected | 1338 | 91.71% |
N408D | 1 | 0.07% | F342Y | 6 | 0.41% | F342Y | 6 | 0.41% |
F412C | 1 | 0.07% | K359E | 1 | 0.07% | T409M | 35 | 2.40% |
F412L | 1 | 0.07% | K359N | 6 | 0.41% | T409M, H411N | 1 | 0.07% |
F412S | 2 | 0.14% | K359E, C592G | 1 | 0.07% | T409M, H411L | 1 | 0.07% |
D413E | 4 | 0.27% | K359N, C480F | 1 | 0.07% | T409M, H411Y | 6 | 0.41% |
D413E, D588N | 3 | 0.21% | E362D | 4 | 0.27% | T409M, C480F | 2 | 0.14% |
P488R | 1 | 0.07% | M460I | 10 | 0.69% | H411L | 3 | 0.21% |
L501I | 6 | 0.41% | M460I, A594S | 1 | 0.07% | H411Y | 30 | 2.06% |
T503I | 6 | 0.41% | M460I, C603W | 2 | 0.14% | H411N/Y | 1 | 0.07% |
T503I, D413E | 1 | 0.07% | M460V/I | 1 | 0.07% | H411Y, C480F | 1 | 0.07% |
T503I, P522S | 1 | 0.07% | M460V | 11 | 0.75% | C480F | 35 | 2.40% |
K513N | 2 | 0.14% | M460V, H520Q | 1 | 0.07% | |||
K513R | 3 | 0.21% | M460V, L595F | 1 | 0.07% | |||
K513T | 1 | 0.07% | M460V, C603W | 2 | 0.14% | |||
I521T | 1 | 0.07% | C480F | 33 | 2.26% | |||
P522S | 12 | 0.82% | C480F, A594V | 2 | 0.14% | |||
del524 | 1 | 0.07% | C480F, C603W | 2 | 0.14% | |||
L545S | 3 | 0.21% | H520Q | 13 | 0.89% | |||
L545W | 3 | 0.21% | H520Q, A594V | 1 | 0.07% | |||
L545S, D301N | 1 | 0.07% | H520Q, L595S | 1 | 0.07% | |||
Q578H | 1 | 0.07% | A591V | 4 | 0.27% | |||
E756K | 1 | 0.07% | C592F | 1 | 0.07% | |||
A834P, G841A, A987G | 1 | 0.07% | C592G | 15 | 1.03% | |||
A987G | 5 | 0.34% | C592G, L595S | 1 | 0.07% | |||
C592G, C603W | 2 | 0.14% | ||||||
A594E | 1 | 0.07% | ||||||
A594P | 5 | 0.34% | ||||||
A594S | 2 | 0.14% | ||||||
A594S, L595S | 1 | 0.07% | ||||||
A594T | 5 | 0.34% | ||||||
A594T, L595W | 1 | 0.07% | ||||||
A594V | 48 | 3.29% | ||||||
A594V, L595F | 1 | 0.07% | ||||||
A594V, L595S | 2 | 0.14% | ||||||
A594V, C603W | 1 | 0.07% | ||||||
del594-598 | 1 | 0.07% | ||||||
del594-603 | 2 | 0.14% | ||||||
L595F | 15 | 1.03% | ||||||
L595F, del599-603 | 1 | 0.07% | ||||||
L595F, C603W | 2 | 0.14% | ||||||
L595S | 71 | 4.87% | ||||||
L595W | 6 | 0.41% | ||||||
del595-599 | 1 | 0.07% | ||||||
del595-603 | 1 | 0.07% | ||||||
del596 | 1 | 0.07% | ||||||
E596G | 1 | 0.07% | ||||||
del600-603 | 1 | 0.07% | ||||||
del601-603 | 1 | 0.07% | ||||||
C603R | 1 | 0.07% | ||||||
C603W | 54 | 3.70% | ||||||
C603W, K359E | 1 | 0.07% | ||||||
C603W, C607F | 1 | 0.07% | ||||||
C607F | 2 | 0.14% |
Anti-CMV Drug and Viral Gene | No. Positive for Resistance | % Positive for Resistance |
---|---|---|
Maribavir UL97 | 121 | 8.29% |
Ganciclovir | 379 | 25.98% |
UL54 mutation(s) only | 26 | 1.78% |
UL97 mutation(s) only | 317 | 21.73% |
Both UL54 and UL97 mutations | 36 | 2.47% |
Maribavir and ganciclovir | 84 | 5.76% |
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Kleiboeker, S.B. Dual Resistance to Maribavir and Ganciclovir in Transplant Recipients. Viruses 2025, 17, 421. https://doi.org/10.3390/v17030421
Kleiboeker SB. Dual Resistance to Maribavir and Ganciclovir in Transplant Recipients. Viruses. 2025; 17(3):421. https://doi.org/10.3390/v17030421
Chicago/Turabian StyleKleiboeker, Steven B. 2025. "Dual Resistance to Maribavir and Ganciclovir in Transplant Recipients" Viruses 17, no. 3: 421. https://doi.org/10.3390/v17030421
APA StyleKleiboeker, S. B. (2025). Dual Resistance to Maribavir and Ganciclovir in Transplant Recipients. Viruses, 17(3), 421. https://doi.org/10.3390/v17030421