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The International Immunecompromised Host Society 23th Biennial Symposium, Antalya, Turkey, 4 - 07 April 2024, pp.107-108, (Full Text)
Background: Human
cytomegalovirus (HCMV) is one of the most common infectious agents in immunocompromised
patients, such as individuals infected with human immunodeficiency virus
(HIV), solid organ or bone marrow transplant recipients. HCMV can cause
retinitis, pneumonia, gastrointestinal disease, and death in these patients.
DNA polymerase inhibitors currently approved for the treatment of HCMV
(valganciclovir/ganciclovir, cidofovir, foscarnet) are associated with
significant toxicities and emergence of drug resistance (1). The new anti-HCMV
drug, letermovir, targets the viral terminase complex and has not reported
cross-resistance with DNA polymerase inhibitors (2). Food and Drug
Administration approved letermovir for prophylaxis of cytomegalovirus (CMV)
infection and disease in adult allogeneic stem cell transplant patients and in
high-risk adult kidney transplant recipients (3).
Mutations conferring resistance to letermovir
consist of amino acid substitutions located mainly in UL56, and rarely in UL89
and UL51 terminase subunits (4). In this study, we aimed to detect basal
mutations in the UL56 gene region in HMCV strains detected in immunodeficient
patients who had not previously received letermovir treatment and evaluate the
effects of these mutations on letermovir resistance.
Method: This study comprised 77 immunocompromised
patients with plasma CMV DNA load of 1000 IU/ml or higher who were admitted to
Hacettepe Hospitals, Ankara, Turkey, between November 2021 and May 2023. Viral
DNA was isolated from all patients’ plasma samples and screened according to
the optimized nested-polymerase chain reaction (PCR) protocol. Target amplicon
size (790 bp) was detected in the samples of 55 patients and sequenced by
Sanger method bidirectionally. The sequences were interpreted using the
Mutation Resistance Analysis platform
(https://dna.informatik.uniulm.de/software/ mra/app/index.php?plugin=form.),
which detects resistance-associated mutations.
Results: This study
consisted of 55 patients, of whom 34 (61.8%) were hematopoietic stem cell
transplant (HSCT) recipients, seven (12.7%) were solid organ transplant
recipients, three (5.6%) were individuals living with HIV and the remaining 11
(20%) had other immunodeficiencies. As a result of the analysis, no letermovir
resistance-associated mutation was detected in these patients. A425V mutation
associated with genetic polymorphism was found in 10 patients (Figure 1).
Except for the A425V mutation, all the sequences obtained from samples were
identical to the reference Human herpesvirus 5 strain Merlin sequence
(Accession Number: NC 006273.2:c87304-84752)
Conclusion: Our
study revealed that basal mutations leading to letermovir resistance were
absent in CMV strains detected in letermovir-naïve immunocompromised patients.
Therefore, letermovir may be an alternative treatment option in immunodeficient
patients who cannot tolerate or are resistant to conventional CMV
therapeutics.
Keywords: CMV, antiviral
resistance, letermovir, immunodeficiency
References
1. Kotton CN, Kumar D, Caliendo AM, Huprikar S,
Chou S, Danziger-Isakov L, et al. The third international consensus guidelines
on the management of cytomegalovirus in solid-organ transplantation.
Transplantation. 2018;102(6):900-31.
2. Lischka P, Hewlett G, Wunberg T, Baumeister J,
Paulsen D, Goldner T, et al. In vitro and in vivo activities of the novel
anticytomegalovirus compound AIC246. Antimicrobial agents and chemotherapy.
2010;54(3):1290-7.
3. FDA U. PREVYMISTM (letermovir) tablet and
injection: NDA approval letter. 2017. 2018.
4. Chou S. Rapid in vitro evolution of human cytomegalovirus UL56
mutations that confer letermovir resistance. Antimicrobial agents and
chemotherapy. 2015;59(10):6588-93.
Acknowledgements: The study was supported by Hacettepe University Scientific Research Projects Coordination Unit (Project no: THD-2022-20069).