letermovir
Sources réglementaires consultées
Indications approuvées
- Prophylaxie du CMV chez les receveurs séropositifs d’une greffe allogénique de cellules souches hématopoïétiques âgés d’au moins 6 mois et pesant au moins 15 kg, et chez les receveurs D+/R− d’une greffe rénale âgés d’au moins 12 ans et pesant au moins 40 kg.
Contre-indications
Absolues
- Association au pimozide ou aux alcaloïdes de l’ergot ; avec la ciclosporine, également pitavastatine, simvastatine, rosuvastatine, atorvastatine ou dabigatran.
- Hypersensibilité au létermovir ou aux excipients.
- Association au millepertuis.
Mises en garde cliniques
- Mise en garde majeure · Il ne traite pas une maladie à CMV établie ; surveiller ADN du CMV et résistance en cas d’infection sous prophylaxie. — CIMA/AEMPS, ficha técnica 1171245001
Interactions médicamenteuses
- SévèreCiclosporine
Mécanisme: Elle augmente le letermovir.
Recommandation: Réduire le letermovir à 240 mg une fois par jour pendant l’association.
CIMA/AEMPS, ficha técnica 1171245001
- SévèreInducteurs puissants ou modérés des transporteurs/enzymes
Mécanisme: Ils peuvent réduire le letermovir et provoquer un échec prophylactique.
Recommandation: Éviter les associations non recommandées.
CIMA/AEMPS, ficha técnica 1171245001
Effets indésirables
Communs (≥1%)
Nausées, diarrhée et vomissements
Rares mais graves
Infection à CMV sous prophylaxie avec résistance
Grossesse et allaitement
Il est préférable d’éviter pendant la grossesse ; décider de l’allaitement selon bénéfice et risque.
Bibliographie récente (PubMed)
Cytomegalovirus (CMV) remains the most important viral pathogen in patients after allogeneic haematopoietic cell transplantation (HCT), resulting in morbidity and mortality. The European Conference on Infections in Leukaemia (ECIL) brings together experts in several fields to produce evidence-based recommendations from comprehensive literature reviews. Management of CMV has been addressed twice before; the previous guideline update from the ECIL was published in 2019. The 10th ECIL meeting in 2024 addressed new developments in CMV management after allogeneic HCT, and recommendations are presented in this Review. Management recommendations include diagnostics, such as immune monitoring, antiviral prophylaxis with letermovir, management of resistant and refractory CMV infections, and paediatric aspects of CMV management. Furthermore, the 10th ECIL introduced recommendations for two new categories: patients treated with chimeric antigen receptor T cells or treated with bispecific T-cell-engaging antibodies.
Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may be worsening with the proportion of high-risk D+/R- solid organ transplantation recipients increasing in some regions globally. Cohort studies continue to support either universal prophylaxis or preemptive therapy as effective prevention strategies. Letermovir prophylaxis was noninferior to valganciclovir in adult high-risk D+/R- kidney transplant recipients with fewer drug-related adverse events in a recent clinical trial and has now been approved for such use in some regions. Maribavir preemptive therapy failed to demonstrate noninferiority when compared with valganciclovir in hematopoietic stem cell transplant recipients but looked promising for safety. Donor matching could be useful in prevention CMV disease with a survival advantage demonstrated in seronegative recipients waiting up to 30 mo for a seronegative kidney. Immune-guided prophylaxis resulted in fewer CMV infection episodes in lung transplant recipients when compared with fixed-duration prophylaxis in a recent clinical trial. For treatment of refractory or resistant CMV infection, maribavir was more efficacious and better tolerated when compared with investigator-initiated therapy in its registration trial for this condition. Further research regarding best treatment and prophylaxis of resistant or refractory CMV infection is needed to reflect best clinical practice choices. Optimal use of immune globulin or CMV-specific T cells for prevention or treatment of CMV disease remains undefined. Standardized definitions for the design of CMV clinical trials have been developed. In this review, we highlight recent updates in the field from data published since 2018.
In a pivotal phase 3 trial of cytomegalovirus prophylaxis with letermovir for up to 100 days after allogeneic haematopoietic stem-cell transplantation (HSCT), 12% of participants developed clinically significant cytomegalovirus infection after letermovir was discontinued. We aimed to evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant cytomegalovirus infection from 100 days to 200 days following HSCT. We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 32 sites in six countries (France, Germany, Italy, Japan, the UK, and the USA). Cytomegalovirus‑seropositive HSCT recipients (aged ≥18 years) who had received letermovir prophylaxis for up to 100 days following HSCT and who remained at high risk of late clinically significant cytomegalovirus infection (with no previous history of clinically significant cytomegalovirus infection, defined as initiation of pre-emptive therapy for documented cytomegalovirus viraemia, onset of cytomegalovirus end-organ disease, or both) were eligible. Participants were randomly assigned (2:1) to receive either an additional 100 days (ie, a total of 200 days; letermovir group) of oral or intravenous letermovir 480 mg once daily, adjusted to 240 mg once daily for participants on cyclosporin A, or 100 days of a placebo comparator for letermovir (ie, a total of 100 days of letermovir; placebo group), following HSCT. Randomisation was done using a central interactive response technology system, stratified by study centre and haploidentical donor (yes or no). Participants, investigators, and sponsor personnel were masked to the treatment allocation. The primary efficacy endpoint was the proportion of participants from randomisation to week 28 (200 days after HSCT) with clinically significant cytomegalovirus infection, analysed using the full analysis set population (ie, those who received at least one dose of study intervention). Safety was analyse
Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT). Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients. Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT.