Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection

Cherrier, Lauren; Nasar, Aasya; Goodlet, Kellie J.; Nailor, Michael D; Tokman, Sofya; Chou, Sunwen

doi:10.1111/ajt.15135

Cited by 110 publications

(93 citation statements)

References 18 publications

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“…In 2011, Kaul and colleagues reported successfully treating a lung transplant recipient with multidrug–resistant CMV disease with letermovir . A case report of a lung transplant recipient described an initial clinical response to letermovir in the setting of ganciclovir‐resistant CMV infection; however, after initial virologic response, the patient developed a UL56 mutation resulting in letermovir resistance . Finally, successful use of letermovir for secondary prophylaxis was reported in a heart transplant recipient with ganciclovir‐resistant CMV disease after clearance of their viremia was achieved with cidofovir and foscarnet …”

Section: Discussionmentioning

confidence: 99%

Single‐center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients

Aryal

Katugaha

Cochrane

et al. 2019

Transplant Infectious Dis

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Background: Cytomegalovirus (CMV) infection is common in thoracic organ transplant recipients. Valganciclovir and ganciclovir are used for both prophylaxis and treatment of this infection, but intolerance and treatment failure are common.Letermovir has been demonstrated to reduce the risk of CMV infection when used for prophylaxis in allogeneic hematopoietic cell transplantation. However, there are no data on its efficacy in thoracic organ transplantation. Methods:We examined the use of letermovir for either CMV prophylaxis (primary and secondary) or treatment in heart and lung transplant recipients at our institution from February 1, 2018, through December 31, 2018. Results: Nine total patients received letermovir at our institution (8 lung transplant, 1 heart transplant) during the study period. Letermovir was prescribed for CMV prophylaxis in eight patients (primary prophylaxis in two patients and secondary prophylaxis in 6 patients), and for treatment of CMV DNAemia in two cases. One patient received letermovir for both secondary prophylaxis and treatment on separate occasions. Three out of 8 (37.5%) patients receiving letermovir for prophylaxis developed CMV DNAemia during prophylaxis. One patient treated for CMV disease had clinical failure with a sharp rise in serum CMV DNA PCR. The other patient treated for lowgrade CMV DNAemia initially had a slight rise in CMV DNA PCR, but has since had a sustained response. No major side effects were experienced, and 2 patients reported minor side effects. Conclusion: Letermovir was well tolerated with only minor side effects reported; however, the rate of development of CMV DNAemia on prophylaxis was considerable. Further study of the dosing and efficacy of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is warranted. K E Y W O R D S cytomegalovirus, heart transplantation, letermovir, lung transplantation 2 of 6 | ARYAL et AL. 1 | INTRODUC TI ON Cytomegalovirus (CMV) infection is a common complication among thoracic organ transplant recipients and often results in increased morbidity and mortality. 1 Ganciclovir and its prodrug, valganciclovir, are used for antiviral prophylaxis after thoracic organ transplantation in recipients with moderate or high risk of CMV infection. They are also the first-line drugs used in the treatment of CMV infection, and both share the same mechanism of action through inhibition of viral DNA polymerase. While these medications are effective, their use is limited by adverse effects and the risk for development of antiviral resistance. It is estimated that 7%-35% of thoracic organ transplant recipients develop leukopenia with 3%-15% of them affected by neutropenia, which can be associated with an increased risk of infection and death. 2 The hematologic complications of valganciclovir/ganciclovir therapy are often compounded by concomitant medication use in transplant recipients. Moreover, therapeutic failure may occur due to the development of resistance mediated by mutations in the genes UL97 and UL54. 3...

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Section: Discussionmentioning

confidence: 99%

Single‐center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients

Aryal

Katugaha

Cochrane

et al. 2019

Transplant Infectious Dis

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“…To date, LMV is approved for HCMV prophylaxis in hematopoietic stem cell transplantation recipients and furthermore represents a promising candidate for future combination therapies or even options of cCMV control [89][90][91][92]. Current points of clinical limitation, however, are the occurrence of LMV-resistant viral mutants [93] and the present lack of an approved treatment option for infants, so that the need for advancements in the development of new antiviral drugs remains.…”

Section: Future Perspective Of the Pharmacological Interference Withmentioning

confidence: 99%

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Marschall

Häge

Conrad

et al. 2020

Viruses

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Herpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric nuclear egress complex (core NEC). These core NECs serve as hexameric lattice-structured platforms for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina as well as membrane-rearranging functions (multicomponent NEC). The regulation of nuclear egress has been profoundly analyzed for murine and human cytomegaloviruses (CMVs) on a mechanistic basis, followed by the description of core NEC crystal structures, first for HCMV, then HSV-1, PRV and EBV. Interestingly, the highly conserved structural domains of these proteins stand in contrast to a very limited sequence conservation of the key amino acids within core NEC-binding interfaces. Even more surprising, although a high functional consistency was found when regarding the basic role of NECs in nuclear egress, a clear specification was identified regarding the limited, subfamily-spanning binding properties of core NEC pairs and NEC multicomponent proteins. This review summarizes the evolving picture of the relationship between sequence coevolution, structural conservation and properties of NEC interaction, comparing HCMV to α-, β- and γ-herpesviruses. Since NECs represent substantially important elements of herpesviral replication that are considered as drug-accessible targets, their putative translational use for antiviral strategies is discussed.

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“…However, their use is limited due to adverse effects such as myelosuppression and nephrotoxicity (3)(4)(5). For the moment, these limitations can be overcome using the novel terminase inhibitor letermovir, yet this therapeutic also is associated with the rapid development of resistance (6)(7)(8)(9). Furthermore, prevention of congenital cytomegalovirus disease is a still unsolved problem (10).…”

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confidence: 99%

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

Stegmann¹,

Rothemund²,

Sampaio³

et al. 2019

J Virol

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The human cytomegalovirus (HCMV) glycoprotein complex gH/gL/gO is required for the infection of cells by cell-free virions. It was recently shown that entry into fibroblasts depends on the interaction of gO with the platelet-derived growth factor receptor alpha (PDGFR␣). This interaction can be blocked with soluble PDGFR␣-Fc, which binds to HCMV virions and inhibits entry. The aim of this study was to identify parts of gO that contribute to PDGFR␣ binding. In a systematic mutational approach, we targeted potential interaction sites by exchanging conserved clusters of charged amino acids of gO with alanines. To screen for impaired interaction with PDGFR␣, virus mutants were tested for sensitivity to inhibition by soluble PDGFR␣-Fc. Two mutants with mutations within the N terminus of gO (amino acids 56 to 61 and 117 to 121) were partially resistant to neutralization. To validate whether these mutations impair interaction with PDGFR␣-Fc, we compared binding of PDGFR␣-Fc to mutant and wild-type virions via quantitative immunofluorescence analysis. PDGFR␣-Fc staining intensities were reduced by 30% to 60% with mutant virus particles compared to wild-type particles. In concordance with the reduced binding to the soluble receptor, virus penetration into fibroblasts, which relies on binding to the cellular PDGFR␣, was also reduced. In contrast, PDGFR␣-independent penetration into endothelial cells was unaltered, demonstrating that the phenotypes of the gO mutant viruses were specific for the interaction with PDGFR␣. In conclusion, the mutational screening of gO revealed that the N terminus of gO contributes to efficient spread in fibroblasts by promoting the interaction of virions with its cellular receptor. IMPORTANCE The human cytomegalovirus is a highly prevalent pathogen that can cause severe disease in immunocompromised hosts. Currently used drugs successfully target the viral replication within the host cell, but their use is restricted due to side effects and the development of resistance. An alternative approach is the inhibition of virus entry, for which understanding the details of the initial virus-cell interaction is desirable. As binding of the viral gH/gL/gO complex to the cellular PDGFR␣ drives infection of fibroblasts, this is a potential target for inhibition of infection. Our mutational mapping approach suggests the N terminus as the receptor binding portion of the protein. The respective mutants were partially resistant to inhibition by PDGFR␣-Fc but also attenuated for infection of fibroblasts, indicating that such mutations have little if any benefit for the virus. These findings highlight the potential of targeting the interaction of gH/gL/gO with PDGFR␣ for therapeutic inhibition of HCMV.

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Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection

Cited by 110 publications

References 18 publications

Single‐center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients

Single‐center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

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