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. 2025 Jul 1;109(7):1066-1110.
doi: 10.1097/TP.0000000000005374. Epub 2025 Apr 9.

The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation

Camille N Kotton  1 , Deepali Kumar  2 , Oriol Manuel  3 , Sunwen Chou  4 , Randall T Hayden  5 , Lara Danziger-Isakov  6 , Anders Asberg  7 , Helio Tedesco-Silva  8 , Atul Humar  2 ; Transplantation Society International CMV Consensus Group
Collaborators, Affiliations

The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation

Camille N Kotton et al. Transplantation. .
No abstract available

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Figures

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Graphical abstract
FIGURE 1.
FIGURE 1.
Suggested options for secondary prevention after an episode of treated CMV DNAemia/disease. In R+ kidney recipients, consider switching from mycophenolate to mTOR and reduce CNI. ALC, absolute lymphocyte count; CMI, cell-mediated immunity; CMV, cytomegalovirus; CNI, calcineurin inhibitor; mTOR, mammalian target of rapamycin; VGCV, valganciclovir.
FIGURE 2.
FIGURE 2.
CMV UL97 kinase gene mutation map. Mutations in bold are most commonly encountered in clinical specimens. Corresponding phenotypes are color coded as shown by the drug abbreviations. Underlined mutations confer increased MBV susceptibility. Updated from previous publication. CMV, cytomegalovirus; GCVr, ganciclovir resistant; MBVr, maribavir resistant.
FIGURE 3.
FIGURE 3.
CMV UL54 DNA polymerase gene mutation map. Most resistance mutations map to conserved structure domains. Their corresponding phenotypes are color coded as shown at the bottom of the figure. Updated from previous publications., CDVr, cidofovir resistant; CMV, cytomegalovirus; FOSr, foscarnet resistant; GCVr, ganciclovir resistant.
FIGURE 4.
FIGURE 4.
CMV UL56 terminase gene mutation map. Letermovir resistance mutations are color coded according to the level of resistance listed under EC50 ratios. Mutations at codon 325 are the most frequent and confer absolute resistance. Updated from previous publication. CMV, cytomegalovirus; EC50, drug concentration required to reduce viral growth by 50% (stated as fold change from baseline).
FIGURE 5.
FIGURE 5.
Flowchart for management of suspected drug-resistant CMV infection. [1] Treatment-refractory: ≤1 log10 decrease in plasma or blood viral load after ≥2 wk of therapy, new or worsening CMV disease. [2] GCV resistance is rare with drug exposure of <6 wk. [3] High viral load: ≥50 000 (4.7 log10) IU/mL (plasma). [4] Avoid FOS if there is renal dysfunction or metabolic intolerance. FOS is suggested for high viral loads in clinically unwell patients. [5] Avoid MBV for CNS disease or retinitis. Treatment-emergent resistance to MBV may limit efficacy. Do not use if any MBV resistance mutations are detected. MBV works better with lower viral loads, see the text. M460I/V, as the sole UL97 mutation, favors the use of MBV. [6] GCV dose 5 mg/kg bid IV, optionally 10 mg/kg bid (high dose), or VGCV dose 900 mg bid, optionally 1800 mg bid (high adult dose; adjusted for renal function). [7] UL56 genotyping If previous exposure to letermovir. [8] Includes sequence variants conferring <2-fold EC50 change. Repeat genotyping with tissue-specific samples for end-organ disease, if available. [9] Consider combination therapy as tolerated. The MBV-GCV combination is antagonistic; do not use it. MBV may be suitable as a step-down treatment after the initial response to FOS when a viral load of <5000 (3.7 log10) IU/mL. Cidofovir performed poorly in a clinical trial, see the text. Letermovir has no clinical trial evidence for efficacy in treating refractory/resistant infection, see the text. Emergent MBV and letermovir resistance is often high grade and requires genotypic monitoring. Other unapproved therapies (weak evidence) include mTOR inhibitors, augmentation of host immunity using adoptive T-cell transfers, and CMV immunoglobulins. CMV, cytomegalovirus; CNS, central nervous system; FOS, foscarnet; GCV, ganciclovir; MBV, maribavir; mTOR, mammalian target of rapamycin; (V)GCV, ganciclovir or valganciclovir.
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References

    1. Kotton CN, Kumar D, Caliendo AM, et al. ; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89:779–795. - PubMed
    1. Kotton CN, Kumar D, Caliendo AM, et al. ; Transplantation Society International CMV Consensus Group. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96:333–360. - PubMed
    1. Kotton CN, Kumar D, Caliendo AM, et al. ; 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. - PubMed
    1. Guyatt GH, Oxman AD, Kunz R, et al. ; GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336:1049–1051. - PMC - PubMed
    1. Guyatt GH, Oxman AD, Vist GE, et al. ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–926. - PMC - PubMed

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